Candidate: Susan Graham, MD, MPH, is a Senior Fellow in Infectious Diseases at the University of Washington (UW) with training in internal medicine and public health and over 4 years of experience in international research. During her fellowship, she has studied HIV-1 genital tract shedding among antiretroviral-treated women in Kenya. Her immediate goals are to complete several prospective cohort studies of the impact of antiretroviral therapy on genital tract shedding, and to complete a doctoral degree in epidemiology. Her long-term objective is to become an independent investigator, leading a research team on the clinical epidemiology, prevention, and treatment of HIV infection in resource-limited settings. Environment: The UW, with its Center for AIDS Research, International AIDS Research and Training Program, and outstanding graduate-level training programs, is ideal for career development in international HIV/AIDS research. Dr. Graham will be supervised by her current mentors, Drs. King Holmes and Scott McClelland, and will collaborate with Dr. Julie Overbaugh's HIV-1 virology laboratory. The Mombasa field site provides administrative infrastructure, strong laboratory support, and a record of having successfully conducted many large epidemiologic studies. A cohort of HIV-1 seropositive patients established by Dr. Graham in a new clinic north of Mombasa provides ample opportunities for development of future projects. Research: In resource-limited settings, patients who fail first-line antiretroviral therapy have limited options and may transmit drug-resistant virus. The proposed prospective cohort study will evaluate the effectiveness of second-line therapy at suppressing HIV-1 replication in both plasma and genital tract secretions. We will evaluate resistance at failure of first-line therapy, subsequent viral suppression by second-line therapy, and correlates of continued HIV-1 genital shedding. Unique aspects of this study include the focus on women at high risk for transmission, enrollment from two ongoing cohorts with data on first-line therapy history, and our group's extensive research experience in studies of HIV-1 genital shedding. Relevance: We propose to study HIV-1 in blood and genital secretions of high-risk women starting second-line antiretroviral therapy. As HIV therapy is scaled up, research on drug resistance and the success of second-line treatment is crucial, and Dr. Graham is poised to make an important contribution in this area..